Short-Term Outcomes following "Switching" to Monthly Ranibizumab in Neovascular Age-Related Macular Degeneration Showing Insufficient Response to ...
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Hindawi
Journal of Ophthalmology
Volume 2021, Article ID 5547686, 8 pages
https://doi.org/10.1155/2021/5547686
Research Article
Short-Term Outcomes following “Switching” to Monthly
Ranibizumab in Neovascular Age-Related Macular Degeneration
Showing Insufficient Response to Bimonthly Aflibercept
Jong Suk Lee ,1,2 Hyun Goo Kang ,3 Christopher Seungkyu Lee ,4 and Se Joon Woo 1
1
Department of Ophthalmology, Seoul National University College of Medicine, Seoul National University Bundang Hospital,
Seongnam, Republic of Korea
2
Nune Eye Hospital, Seoul, Republic of Korea
3
Department of Ophthalmology, Institute of Vision Research, Gangnam Severance Hospital,
Yonsei University College of Medicine, Seoul, Republic of Korea
4
Department of Ophthalmology, Institute of Vision Research, Severance Eye Hospital, Yonsei University College of Medicine,
Seoul, Republic of Korea
Correspondence should be addressed to Christopher Seungkyu Lee; sklee219@yuhs.ac and Se Joon Woo; sejoon1@snu.ac.kr
Received 13 January 2021; Revised 14 July 2021; Accepted 29 July 2021; Published 12 August 2021
Academic Editor: Dirk Sandner
Copyright © 2021 Jong Suk Lee et al. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Background/Objectives. To evaluate the efficacy of switching to monthly ranibizumab in neovascular age-related macular de-
generation (nAMD) showing an insufficient response to bimonthly aflibercept. Subjects/Methods. A total of 13 nAMD eyes
showing an insufficient treatment response to three successive aflibercept injections were enrolled through a retrospective chart
review. After switching, three consecutive monthly intravitreal ranibizumab injections were performed. The main outcome
measurements included the best-corrected visual acuity (BCVA), central retinal thickness (CRT), presence of intraretinal fluid
(IRF), and subretinal fluid (SRF) using optical coherence tomography (OCT) and were measured every month. Results. CRT and
logMAR VA were 349.62 ± 223.51 μm and 0.50 ± 0.23 at the baseline and 274.69 ± 148.77 μm and 0.46 ± 0.24, 311.54 ± 192.90 μm
and 0.45 ± 0.20 at 1 month after the first and third ranibizumab injections, respectively. The CRT decrease during three
ranibizumab injections was statistically significant (38.08 ± 69.52 μm, p � 0.033). Change in VA was not statistically significant.
The percentage of eyes with SRF was 100% at baseline and 53.8%, 76.9%, and 69.2% one month after each ranibizumab injections.
The percentage of eyes with IRF was 38.5% at baseline and 23.1%, 23.1%, and 15.4%, respectively, after switching. Conclusion.
Switching to monthly ranibizumab in nAMD showing an insufficient response to bimonthly aflibercept led to immediate
anatomical improvement. It can be considered in countries where the healthcare insurance system limits the minimum injection
interval of aflibercept.
1. Introduction several years later. The calculated duration of the effect of a
single intravitreal injection of 2 mg aflibercept was reported
Age-related macular degeneration (AMD) is one of the to be 48–83 days due to its higher affinity for VEGF and
significant causes of blindness worldwide. The gold standard longer half-life compared with both bevacizumab and
treatment for neovascular age-related macular degeneration ranibizumab [3, 4]. Monthly or bimonthly intravitreal
(nAMD) is an intravitreal antivascular endothelial growth aflibercept injections demonstrated similar therapeutic ef-
factor (VEGF) therapy. Intravitreal anti-VEGF medications fects as monthly intravitreal ranibizumab injections [5].
bevacizumab and ranibizumab are first introduced and Based on these reports, the health insurance system in many
recognized for improving visual and anatomical outcomes in countries, including Korea, sets a minimum intravitreal
patients with nAMD [1, 2]. Aflibercept was introduced injection interval of 2 months for aflibercept.
2 Journal of Ophthalmology
However, in some patients, the intravitreal injection was observed at least once after initiation of anti-VEGF
effect of aflibercept is not maintained for 2 months. Fauser treatment for nAMD, and the SRF recurred while maintaining
et al. [6] reported that the intraocular VEGF concentrations bimonthly aflibercept treatment.
were suppressed below the lower limit of quantification
(4 pg/mL) after intravitreal aflibercept injections for about
10 weeks on average. However, this study showed that the 2.2. Study Design. Three consecutive ranibizumab (0.5 mg/
VEGF suppression effect by aflibercept could be shorter 0.05 ml) doses were administered by monthly intravitreal
than two months in some patients. The real-world data of injection at “baseline” (the day determined to “switch,” 2
treatment and extend (T&E) treatment for nAMD using months after the last aflibercept injection), “1 month”
aflibercept also shows a subgroup of patients who need (30–37 days after first ranibizumab injection), and “2
treatment at intervals shorter than two months [7]. As a months” (30–37 days after second ranibizumab injection).
result, more frequent anti-VEGF treatment is necessary for Visual acuity (VA) and optical coherence tomography
these patient groups. In South Korea, where the solitary (OCT) measurements were conducted at baseline, 1 month,
national health insurance system has limited the minimum 2 months, and 3 months (30–37 days after the third rani-
interval of aflibercept treatment to two months, switching bizumab injection; Figure 1). From 3 months after switching
to monthly ranibizumab treatment or additional bev- (1 month after third ranibizumab injection), one of the
acizumab treatment might be required for these patients. In following treatment methods was applied to each patient
most other countries, the health insurance system is not as according to the monthly ranibizumab treatment response:
simple as that of Korea, and the policies of several private maintaining monthly ranibizumab treatment, ranibizumab
health insurance companies are diverse and constantly treatment with an extended injection interval, or reswitching
changing. However, previous studies using real-world data to an aflibercept-based treatment (bimonthly aflibercept or
confirmed that, in many countries, the minimum dosing monthly aflibercept or monthly cross-injection with
interval of aflibercept is limited to 2 months. Europe, es- bevacizumab).
pecially the United Kingdom, is a representative example
(SAFARI study) [8].
Although there have been several reports about the 2.3. Efficacy Assessments. The main outcome measurements
therapeutic effect of switching from ranibizumab to afli- (primary efficacy variables) included VA and central retinal
bercept [9–14] or switch-back to ranibizumab [15, 16], data thickness (CRT) using spectral-domain optical coherence
on switching from bimonthly aflibercept to monthly rani- tomography (SD-OCT, Spectralis OCT; Heidelberg Engi-
bizumab are sparse. Although most previous studies have neering, Heidelberg, Germany). The secondary efficacy
reported favorable outcomes after switching from ranibi- variables included the proportion of eyes with remnant or
zumab to aflibercept, it is possible that the disease’s natural recurrent intraretinal fluid (IRF) and subretinal fluid (SRF)
course and “anti-VEGF resistance” were involved in addi- to confirm the patient’s retinal morphology before and after
tion to the drug’s effects. switching.
This report evaluates the switching effect in terms of
“anti-VEGF resistance” and the efficacy of monthly rani-
bizumab treatment in patients with nAMD showing an 2.4. Statistical Analysis. To evaluate the anatomical and
insufficient treatment response to bimonthly aflibercept; we functional efficacy of three monthly ranibizumab treat-
investigated the anatomical and functional outcomes after ments, CRT and VA of “1 month” and “3 months” were
switching from bimonthly aflibercept to monthly compared to “baseline.” Due to the small number of patients
ranibizumab. and nonnormal distribution of the observed data for the
CRT and VA, the Wilcoxon signed-rank test was used.
Statistical significance was defined as a p value < 0.05. All
2. Materials and Methods statistical analyses were performed using SPSS version 24.0
2.1. Participants. Eligible patients were ≥50 years of age with (SPSS Inc., Chicago, USA).
nAMD who visited Seoul National University Bundang
Hospital and Severance Eye Hospital. The patients had a 3. Results
macula-involving active choroidal neovascularization lesion
secondary to typical AMD or polypoidal choroidal vasculop- We identified 13 eyes from 13 patients with neovascular
athy (PCV) in the study eye. Insufficient responders to afli- AMD (including 6 eyes of PCV) showing an insufficient
bercept were defined as those with subretinal fluid remaining treatment response to aflibercept treatment. These patients
or increasing despite more than three successive injections of showed remaining or increasing SRF during three consec-
aflibercept (2.0 mg/0.05 ml) at 1- or 2-month intervals, and the utive successive aflibercept intravitreal injections before
last injection was performed bimonthly before switching to switching and received three consecutive monthly ranibi-
ranibizumab. As a result, eligible patients who received three zumab intravitreal injections. Of the 13 eyes, three cases
consecutive successive injections of aflibercept injections im- were included in which the interval between the first 2 out of
mediately before switching were enrolled, regardless of the 3 consecutive aflibercept injections was 1 month. The de-
treatment history (other anti-VEGF injections or photody- mographics and treatment history of the enrolled patients
namic therapy (PDT)). In all enrolled patients, dry-up of SRF are summarized in Table 1.
Journal of Ophthalmology 3
Switching
-4 month -2 month Baseline 1 month 2 month 3 month 4 month
Injection
CRT
measure
IRF, SRF
Aflibercept (bimonthly)
Ranibizumab (monthly)
Figure 1: Flow diagram showing the schedule of intravitreal injections and OCT measurements of the enrolled eyes with nAMD. CRT,
central retinal thickness; IRF, intraretinal fluid; SRF, subretinal fluid.
Table 1: Clinical and demographic characteristics of included (0.07 ± 0.12) was not statistically significant (p � 0.114,
patients with neovascular age-related macular degeneration Wilcoxon signed-rank test) (Figure 2).
showing an insufficient response to bimonthly aflibercept.
Characteristic Mean or number
3.2. Secondary Efficacy Variables. SRF was observed in the
11 : 2
Male-to-female ratio, no. (%) baseline OCT in all enrolled eyes. At “1 month” (1 month
(84.6% : 15.4%)
Mean age at baseline (y) 72.77 ± 8.27 after the 1st ranibizumab injection), the proportion of eyes
Type of nAMD, typical nAMD : PCV (%) 7 : 6 (53.8% : 46.2%) with SRF decreased dramatically. In 53.8% of the enrolled
Average number of previous anti-VEGF eyes, SRF was completely absorbed, and 46.2% of the en-
injections rolled eyes showed residual SRF. However, despite con-
Aflibercept 8.08 ± 4.97 tinuing monthly ranibizumab injection, the tendency of SRF
Ranibizumab 2.00 ± 4.10 recurrence was observed at 1 month after second and third
Bevacizumab 5.38 ± 11.1 ranibizumab treatment. The height of the recurrent SRF was
Previous PDT (%) 2 (15.4%) not higher than that of the baseline (Figures 3 and 4). Re-
Baseline central retinal thickness, μm 349.62 ± 223.51
sidual IRF was observed in 38.5% of the enrolled eye at
Baseline best-corrected visual acuity,
logMAR
0.50 ± 0.23 baseline. The proportion of eyes with residual IRF gradually
decreased to 15.4% at 1 month after the third ranibizumab
nAMD, neovascular age-related macular degeneration; PCV, polypoidal
choroidal vasculopathy; R, right; L, left; A, aflibercept; B, bevacizumab;
injection.
PDT, photodynamic therapy.
3.3. Long-Term Maintenance of Treatment after Switching.
3.1. Primary Efficacy Variables. The average CRTs at The long-term efficacy was assessed in 12 eyes that had been
baseline and 1 month after each ranibizumab injection followed up for 1 year after switching. Among the 12 eyes, 6
were 349.62 ±223.51 μm, 274.69 ± 148.77μm, 330.62± eyes (50%) maintained ranibizumab treatment for 1 year,
240.02 μm, and 311.54 ± 200.77 μm, respectively. The and the remaining 6 (50%) were reswitched to aflibercept-
differences between the average CRT at baseline and av- based treatment due to an insufficient response to monthly
erage CRT at 1 month and 3 months (1 month after third ranibizumab or patients’ unwillingness to maintain monthly
ranibizumab injection) after the switching were statisti- treatment. Of the 6 eyes treated with ranibizumab, 4
cally significant (74.92 ± 88.74 μm, p � 0.002 and maintained monthly ranibizumab for 1 year and 2 extended
38.08 ± 69.52 μm, p � 0.033, Wilcoxon signed-rank test). the injection interval. The remaining six eyes were changed
Figure 2 shows changes in individual and in average CRT to an aflibercept-based regimen during the 1 year follow-up
and average BCVA. The average CRT most remarkably period. At the last visit, four of them were cross-injected with
decreased 1 month after the switch and slightly increased aflibercept and bevacizumab every month. One eye main-
for the second month. The differences in CRT between 1 tained bimonthly aflibercept, and the other maintained
and 2 months and 2 and 3 months were not statistically monthly aflibercept. The average number of monthly
significant (p � 0.120 and 0.074, respectively). The treat- ranibizumab maintenance for 1 year after switching was
ment response based on CRT worsened in two patients 8.67 ± 2.90 (Figure 5).
three months after the switching, and transient aggrava-
tion after the second ranibizumab injection was observed 4. Discussion
in eight patients.
The average LogMAR VA at baseline and 1, 2, and 3 Switching to monthly ranibizumab with three consecutive
months were 0.50 ± 0.23, 0.46 ± 0.24, 0.49 ± 0.25, and injections in patients with nAMD showing an insufficient
0.45 ± 0.20, respectively. The average VA tended to improve response to bimonthly aflibercept led to immediate ana-
after switching, but the average VA difference between tomical improvement, especially in the first month after
baseline and 1 month after the third ranibizumab injection switching. Two months after switching, CRT and SRF tended
4 Journal of Ophthalmology
Change in mean BCVA
Change in mean CRT
400 0.51
0.50 ± 0.23
0.5
0.49 ± 0.25
0.49
(LogMAR unit)
349.62 ± 223.51 0.48
350
330.62 ± 240.02 0.47
(µm)
0.46
0.46 ± 0.24
300 311.54 ± 200.77 0.45
0.45 ± 0.20
0.44
0.43
274.69 ± 148.77
250 0.42
Baseline 1 Month 2 Month 3 Month Baseline 1 Month 2 Month 3 Month
Change in CRT of individual patients
1200
1000
800
600
400
200
0
Baseline 1 Month 2 Month 3 Month
CFT(um) CFT(um) CFT(um) CFT (um)
1 6 11
2 7 12
3 8 13
4 9
5 10
Figure 2: Changes in central retinal thickness (CRT) and visual acuity (VA) after switching from bimonthly aflibercept to monthly
ranibizumab. The figures on the top show the change in average central retinal thickness (CRT) and best-corrected visual acuity (BCVA).
The bottom figure shows the change in CRT in individual patients.
to increase slightly again, indicating the switching effect’s Apart from comparing anti-VEGF agents in patients
decay after repeated injections. with treatment-naı̈ve nAMD, there have been studies related
There have been several reports comparing the thera- to the treatment response after anti-VEGF agent switching.
peutic effects of ranibizumab and aflibercept in treatment- A minority of patients with nAMD experience suboptimal
naı̈ve patients with nAMD. In these studies, equivalent treatment response to continued therapy with the same anti-
therapeutic effects (in terms of functional and morphologic VEGF agent (anti-VEGF resistance) [20–23]. Since afli-
outcomes) and a similar injection burden were observed bercept was introduced a few years later than ranibizumab
between ranibizumab and aflibercept [17–19]. It is also well and showed a higher affinity for VEGF, there have been
known that monthly or bimonthly intravitreal aflibercept many reports about the therapeutic effects of switching from
injections demonstrated similar therapeutic effects as ranibizumab to aflibercept [9–14]. Bakall et al. [10] and
monthly intravitreal ranibizumab injections [5]. In PCV, Grewal et al. [11] reported anatomical improvement after
aflibercept treatment was more effective than ranibizumab switching to aflibercept in patients with nAMD resistance to
for polyp regression [19]. other anti-VEGF agents, bevacizumab and ranibizumab.
Journal of Ophthalmology 5
100 100
80
76.9
69.2
60
(%)
53.8
40
38.5
23.1 23.1
20 15.4
0
Baseline 1 Month 2 Month 3 Month
Ranibizumab injection
SRF
IRF
Figure 3: The proportion of eyes with subretinal fluid (SRF) and intraretinal fluid (IRF) after “switching.”
Case 1 Case 2 Case 3
Baseline Baseline Baseline
1 month 1 month 1 month
2 month 2 month 2 month
3 month 3 month 3 month
Aflibercept (bimonthly)
Ranibizumab (monthly)
Figure 4: OCT findings of the typical cases showing a short-term anatomical good response after “switching” to monthly ranibizumab. One
month after the first intravitreal ranibizumab injection, subretinal fluid (SRF) was dramatically decreased, and in 75%, it was completely
absorbed. In 33.3%, no SRF recurred during 3 months after switching, as in case 1. Despite the consecutive monthly ranibizumab treatment,
SRF recurrence was observed after the second intravitreal ranibizumab injection, as in cases 2 and 3. However, after 3 consecutive monthly
ranibizumab injections, the height of the recurrent SRF was less than that of the baseline, and the final average CRT shows a statistically
significant decrease compared to the baseline.
However, potential factors explaining this favorable out- Few studies have been conducted on the therapeutic
come after switching include tachyphylaxis, the natural effects of reverse switching from aflibercept to ranibizumab.
course of the disease, and injection pattern, as well as the The therapeutic effect of switching back to bevacizumab or
difference in the anti-VEGF agent itself. One of enrolled ranibizumab for recurrent neovascular activity with afli-
patients visited the clinic one month after the last aflibercept bercept in nAMD was reported to be initially effective [15].
treatment and showed a favorable anatomical outcome 1 Recently, Gale et al. [8] suggested that patients with nAMD
month before “switching,” which means that not only the who have shown a suboptimal response to aflibercept may
drug itself but also the injection interval affects the thera- benefit from switching to ranibizumab. This study con-
peutic effect of anti-VEGF agents in nAMD (Figure 6). firmed that the switching from aflibercept to ranibizumab
6 Journal of Ophthalmology
Re-switch to Aflibercept Maintain Ranibizumab
Monthly Ranibizumab
Extended Ranibizumab
Bimonthly Aflibercept
Monthly Aflibercept
Cross-injection using Aflibercept and Bevacizumab
Figure 5: Treatment patterns 1 year after switching.
(a) (b)
(c) (d)
Figure 6: Treatment response 1 month after last aflibercept injection (1 month before “switching” to ranibizumab). (a) The OCT findings at
the time of the last aflibercept injection. (b) The OCT findings 1 month after the last aflibercept injection. (c) The OCT findings at the time of
the first ranibizumab injection after “switching.” (d) The OCT finding 1 month after the first ranibizumab injection. (b) shows a favorable
anatomical outcome 1 month after the aflibercept injection, which means that not only the drug itself but also the injection interval affects
the therapeutic effect of anti-VEGF agents in nAMD.
led to a significant improvement in CRT, with approxi- the presence of subfoveal SRF had little impact on mean
mately 60% experiencing stabilized or improved best-cor- visual acuity, and those with persistent SRF also seemed to
rected visual acuity (BCVA), although this was maintain their vision in the long-term [25, 26]. Although the
counterbalanced by a large minority (38%) who lost ≥1 thickness of the retina gradually increased from 1 month
letter. The most remarkable improvement in clinical out- after switching, it is possible that the final BCVA, 3 months
comes was observed during the initial monthly treatment after the switching point, improved due to the gradual
period. absorption of IRF.
Our findings concur with these previous reports and The results of “Long-term maintenance of treatment
suggest that the favorable treatment outcome of switching after switching” show that in 50%, the treatment results of
from bimonthly aflibercept to monthly ranibizumab might ranibizumab were satisfactory, and the other 50% was
be related to anti-VEGF resistance. In addition, in our study, reswitched due to the decay in the treatment response or the
a group of patients had BCVA improved, and the change in patient could not maintain the monthly injections. There-
average BCVA was not statistically significant but showed a fore, although the short-term effect of switching to monthly
tendency to improve after 3 monthly injections of ranibi- ranibizumab showed a favorable response in the refractory
zumab compared to baseline. According to many previous cases, the efficacy tended to reduce gradually, and the long-
studies about nAMD and visual outcomes, IRF had a much term maintenance of monthly ranibizumab treatment might
greater negative impact on the BCVA than SRF [24], while not be feasible in the real-world situation.
Journal of Ophthalmology 7
As many new anti-VEGF agents with longer half-lives are are available through the reapproval process of the IRB and
continuously being developed, it is important to elucidate the the corresponding author upon request.
differences in therapeutic effects between different anti-VEGF
agents. Because new anti-VEGF agents can be injected not Ethical Approval
only to treatment-naı̈ve patients but also to patients treated
with existing agents, studies about the clinical effectiveness of This study was approved by the Institutional Review Board
anti-VEGF resistance and the switching effect between var- of Seoul National University Bundang Hospital and Sev-
ious anti-VEGF agents should be conducted. Monthly afli- erance Eye Hospital, and the tenets of the Declaration of
bercept treatment and combination of aflibercept and Helsinki were followed.
ranibizumab or bevacizumab can be appropriate treatment
options for some patients. In addition, a shift to new anti- Consent
VEGF agents, such as brolucizumab, which are expected to be
more effective in nAMD refractory to conventional anti- Informed consent was waived because of the retrospective
VEGF agents, can be an alternative option [27]. nature of the study and the analysis used anonymous clinical
The effectiveness of switching can be evaluated by CRT data.
changes in the short-term and the reswitching rate in the
long-term. In order to determine the characteristics of pa- Disclosure
tients with poor treatment response or anti-VEGF resistance,
we evaluated the age, subtype of nAMD, and the type or total The funding organization had no role in the design or
number of anti-VEGF injections, especially previous rani- conduct of this study.
bizumab injections. However, we observed no significant
correlations. Furthermore, well-designed prospective or Conflicts of Interest
comparative studies are warranted to identify the long-term
The authors declare that they have no conflicts of interest.
effect of switching, the duration of single anti-VEGF agent
treatment before anti-VEGF resistance, and the selection of
ideal anti-VEGF agents. In addition, a unified criterion of Authors’ Contributions
treatment failure for a specific anti-VEGF agent that can be Christopher Seungkyu Lee and Se Joon Woo contributed
used as the basis for regimen change should be established. equally to this work.
This study has several limitations. First, it is a retrospective,
noncomparative case series that included a small number of
cases. Moreover, there was no comparative data with monthly
Acknowledgments
aflibercept treatment because of the Korean National Health This work was supported by the National Research Foun-
Insurance System’s restriction. Therefore, it is impossible to dation (NRF) of Korea grant funded by the Korea Gov-
determine whether switching is due to anti-VEGF agents’ ernment (MSIT) (2020R1F1A1072795).
change or injection schedules. We enrolled patients with
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